A new patient-reported outcomes instrument for assessing toxicities in oncology trials ultimately could create an opportunity for comparative tolerability claims across cancer treatments.

The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is an electronic-based system for patient self-reporting of symptomatic adverse events. It is being developed by the National Cancer Institute in conjunction with clinical trial networks and regulatory partners, including FDA, to improve the accuracy and precision of adverse event grading.

NCI plans to make four language versions of the PRO-CTCAE publicly available in the first quarter.

PRO-CTCAE is a standard yet flexible instrument that can generate descriptive patient-reported AE symptom data, FDA Office of Hematology and Oncology Products Acting Deputy Director Paul Kluetz said at the recent Friends of Cancer Research/Brookings Center for Health Policy Conference on Clinical Cancer Research.

The instrument is suitable for descriptive labeling of AEs that would complement other types of side effect data in labeling, he said.

Since the PRO-CTCAE is aimed at assessing drug toxicities, the tool would not provide the basis for an efficacy claim.

However, PRO-CTCAE data might someday be used to support a comparative tolerability labeling claim, Kluetz said, adding that more work would be needed to determine the appropriate trial design and other data necessary to support such a comparison statement.

Turning The Tide On PROs In Oncology

Although FDA finalized a guidance on patient-reported outcomes to support labeling claims in 2009, few oncology drugs actually reflect such data in their labels Also see "Patient-Reported Outcomes in Oncology: The Jakafi and Zytiga Exceptions" - Pink Sheet, 24 November, 2014..

Measuring patient-reported outcomes in cancer clinical trials can be inherently difficult due to a number of factors, including often significant toxicities associated with treatment and single-arm trial designs that make interpretation of such data challenging.

Challenges with using currently available PROs in this setting include a lack of standardization of data collection and analysis, use of instruments that target more general concepts and not those specifically tailored to the condition at issue, and problems with large amounts of missing data.

FDA's oncology/hematology office has become increasingly interested in working with industry and other stakeholders to advance PRO assessments Also see "FDA Oncology Office Hopes Better Advice Will Lead To More Patient-Reported Outcomes Data" - Pink Sheet, 13 April, 2015..

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The agency intends to convene a public workshop April 26 to discuss the overall PRO strategy in international cancer trials, with a particular focus on symptomatic adverse events and patient-reported physical function (see sidebar).

Development and use of PRO-CTCAE, which is derived from an existing clinician-reported outcomes instrument, is expected to be part of the discussion at that meeting.

CTCAE's Offspring

Adverse events in oncology trials currently are assessed and reported by investigators using a standard method developed by NCI known as the CTCAE.

CTCAE contains approximately 800 individual AEs that are graded for severity and impact on a scale of 1-5. Data on the incidence and severity of important and frequent AEs as measured by the CTCAE are included in product labeling.

However, "there is substantial evidence that clinicians under-detect the prevalence and severity of subjective symptoms such as pain and fatigue, and that clinicians’ failure to note these symptoms can result in unnecessary harm to patients," a multi-stakeholder panel said in an issue brief presented at the FOCR/Brookings conference Nov. 17.

The PRO-CTCAE is intended as a companion to the CTCAE to improve the precision and patient-centeredness of the existing instrument.

The patient-reported instrument comprises an item library containing 78 symptomatic AEs drawn from the CTCAE. Each symptomatic AE has one to three items, such as frequency, severity and interference with activities (see graphic).

Source: Basch E, et al. Capturing Symptomatic Adverse Events From the Patients’ Perspective: The Potential Role of the National Cancer Institute’s PRO-CTCAE Measurement System. Issue Brief developed for Friends of Cancer Research/Brookings Annual Meeting, November 2015.

The tool also includes a software system that can be used to create customized surveys and allows for patient interface via web or interactive voice response.

At the FOCR/Brookings conference, Sandra Mitchell, a research scientist at NCI's Outcomes Research Branch, said that over the past several years PRO-CTCAE has been developed into a psychometrically robust library of items with a data collection process that fits smoothly into clinical trial workflow. The tool can accommodate individuals with limited proficiency in English and digital literacy, and it can supply meaningful data to improve understanding of symptomatic AEs, she said.

More than 100 early adopters in academic settings and industry-sponsored studies are testing the instrument in treatment trials and observational studies.

Mitchell said the patient-reported tool can be used throughout a product's clinical development (see box).

PRO-CTCAE's Utility Through The Phases

Phase I: Provide a preliminary profile of symptomatic side effects to inform development of measurement approaches for later-stage studies
Phase II: Describe toxicity in depth to identify means for reducing symptomatic side effects and profiling chronic Grade 2 toxicities
Phase III: Evaluate tolerability and assess strategies for minimizing chronic Grade 2 toxicities that may impair adherence
Phase IV: Optimize tolerability and tailor regimens for those with co-morbidities or frailties

Ethan Basch, director of cancer outcomes research at the University of North Carolina, described the experience with PRO-CTCAE in an ongoing clinical trial comparing chemoradiotherapy to chemotherapy alone in patients with locally advanced rectal cancer. The PRO-CTCAE data were compared against the CTCAE results for the adverse events of diarrhea and neuropathy.

The PRO-CTCAE showed a greater degree of severe diarrhea than did the CTCAE. In addition, the patient-reported instrument showed more profound differences between study arms in the occurrence of neuropathy and revealed a greater degree of severe neuropathy than the clinician-reported instrument, he said.

"One could argue that I and my colleagues are missing a lot of the more severe neuropathy or effectively systematically downgrading it," Basch said.

Another advantage to the PRO-CTCAE is that it picks up baseline symptoms that can be subtracted in the final analysis of a treatment's toxicity profile, he said.

"I would argue the PRO-CTCAE provides a more precise way to delineate the toxicities between clinical trial arms," Basch said. "This is a very well developed tool that captures the patient experience with toxicities in cancer trials and I feel it is ready to be implemented now, today, with a couple of practical considerations."

Will Industry Embrace It?

Now that standard analytic validation of the PRO-CTCAE has been completed, NCI plans to make English, Spanish, German and Japanese language versions of the tool publicly available in the first quarter 2016 so that it can be incorporated into oncology clinical trials, Mitchell said.

However, interpretation and clinical utility of PRO-CTCAE is still evolving and work is underway on a number of issues, including evaluating different approaches to analyzing and representing PRO-CTCAE data, testing additional items to expand the library, and development and validation of the instrument in six additional languages, Mitchell said.

Alicyn Campbell, global head of patient outcomes research for oncology at Genentech Inc., said it would be important to have a single PRO measure that would satisfy regulators across the globe. However, the limited number of languages in which the PRO-CTCAE is initially available likely will hinder industry adoption, she said.

Campbell suggested creation of a pre-competitive industry collaboration whereby multiple sponsors would share in the upfront cost of translations and pay no future usage fees, while nonparticipating sponsors would pay usage fees to supplement future languages.

Other technical barriers to industry adoption include the need for a data-driven rationale for selecting PRO-CTCAE items for inclusion in a given study to minimize responder burden and prevent multiplicity, Campbell said.

In addition, there needs to be agreement on data collection standards, such as enabling and coding patient write-in responses, as well as data analysis standards, including consensus on data scoring, how the analyses will be presented and cross-trial comparison methods when differing item sets are included, she said.

Descriptive Labeling Versus Labeling Claims

FDA's Kluetz said that while the PRO-CTCAE instrument provides data that are suitable for descriptive labeling of AEs, it also could be used in drug-versus-drug comparisons of tolerability.

However, "that design is going to be the most challenging to describe how to do because it's not only individual adverse events and the sum of those, but there has to be some way for us to say overall … group A felt that this drug was 50% tolerable and group B though it was 25% tolerable," Kluetz said.

"That endpoint is what we all have to discuss, the summation of the adverse events, the summation of how they experienced therapy."

However, there are concerns that merely describing the PRO data in labeling without a formal claim may not be enough to incentivize sponsors to incorporate the instrument in trials.

FOCR Chair and Founder Ellen Sigal said sponsors are unlikely to conduct comparative tolerability studies because they are difficult and expensive. "At the end of the day for people to be incented to do this properly and to do it rigorously and for people to evaluate it, that label Is going to be incredibly important," she said.

Kluetz acknowledged that there might be an "incentive problem" for sponsors to use the PRO-CTCAE unless it can support a labeling claim.

"But I would like to point out this isn't something we're asking that's not already being done," he said, referring to current PRO data collection efforts. "It's just being done suboptimally, in my opinion."

Oncology Patient-Reported Outcomes Tool May Lead To Comparative Tolerability Claims

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